To date, a variety of beta-lactam drugs have been developed and beta-lactam drugs have become clinically extremely important antimicrobial drugs. However, there are increasing number of bacterial types which have obtained resistance against beta-lactam drugs by producing beta-lactamase, which degrade beta-lactam drugs.
According to the Ambler molecular classification, beta-lactamases are largely classified into four classes. Specifically, these are Class A (TEM type, SHV type, CTX-M type, KPC type and the like), Class B (IMP type, VIM type, L-1 type and the like), Class C (AmpC type) and Class D (OXA type and the like). Amongst these, Classes A, C and D types are largely classified into serine-beta-lactamase, on the other hand, Class B type is classified into metallo-beta-lactamase. It has been known that both have respectively different mechanisms to each other in terms of hydrolysis of beta-lactam drugs.
Recently, clinical problem has been occurring due to the existence of Gram negative bacteria which have become highly resistant to a number of beta-lactam drugs including Cephems and Carbapenems by producing Class A (ESBL) and D types serine-beta-lactamases which have an extended substrate spectrum, and Class B type metallo-beta-lactamase which have an extended substrate spectrum. Particularly, metallo-beta-lactamase is known to be one of the causes of obtaining multidrug-resistance in Gram negative bacteria. Cephem compounds which exhibit intermediate activity against metallo-beta-lactamase producing Gram negative bacteria are known (e.g., International Publication No. 2007/119511 pamphlet and Applied Microbiology and Biotechnology (1994), 40(6), 892-7). However, there is a demand for development of Cephem compounds which exhibit more potent antimicrobial activity, in particular more effective against a variety of beta-lactamase producing Gram negative bacteria.
One of the known antimicrobials having high anti-Gram negative bactericidal activity is Cephem compounds having a catechol group intramolecularly (e.g., The Journal of Antibiotics, vol. 61, pp. 36-39 (2008); The Journal of Antibiotics, vol. 43, pp. 1617-1620 (1990) The Journal of Antibiotics, vol. 42, pp. 795-806 (1989)). The action thereof is that the catechol group forms a chelate with Fe3+, thereby the compound is efficiently incorporated into the bacterial body through the Fe3+ transportation system on the cellular membrane (tonB-dependent iron transport system). Therefore, research has been conducted on compounds having catechol or similar structure thereto, on the 3-side chain or 7-side chain moiety on the Cephem backbone.
Examples in the non-patent literature (i.e., e.g., see, Applied Microbiology and Biotechnology (1994), 40(6), 892-7) and patent literature (i.e., see Japanese Laid-Open Publication No. 4-364189; Japanese Laid-Open Publication No. 3-173893; Japanese Laid-Open Publication No. 2-15090; Japanese Laid-Open Publication No. 2-28187; Japanese Laid-Open Publication No. 2-117678; Japanese Laid-Open Publication No. 2-28185), respectively, describe catechol type derivatives having a catechol group on the 3-side chain moiety on the Cephem backbone. Other patent documents (i.e., e.g., Japanese Laid-Open Publication No. 2-15090; Japanese Laid-Open Publication No. 2-28187; Japanese Laid-Open Publication No. 6-510523; and Japanese Laid-Open Publication No. 5-213971) describe pseudo-catechol type derivatives having a hydroxypyridone group on the 3-side chain moiety on the Cephem backbone. Patent Documents, International Publication No. 2007/096740 pamphlet and International Publication No. 2003/078440 pamphlet disclose Cephem compounds having a quaternary ammonium group, but do not describe a catechol type derivative.
Moreover, in the above documents, which describe Cephem compounds having a catechol group in their structure, there is no description of Class B type metallo-beta-lactamase and specific antimicrobial activity against a wide variety of Gram negative bacteria including Class B type.
Additionally, specific patent literature documents (i.e., e.g., European Patent Publication No. 35357 and U.S. Pat. No. 3,487,079) and non-patent literature documents (i.e., e.g., Chemical & Pharmaceutical Bulletin, vol. 31, 1482-1493 (1983); Journal of Medicinal Chemistry, vol. 14, 420-425 (1971); and International Journal of Peptide & Protein Research, vol. 10, 51-59 (1977)), respectively, describe cephem compounds having a substituent at position 2 of the cephem skeleton. However, these compounds do not have a quaternary ammonium group and a catechol group at position 3 of the cephem skeleton.
Non-patent literature (e.g., The Journal of Antibiotics, vol. 41, pp. 1154-1157 (1988); The Journal of Antibiotics, vol. 43, pp. 357-371 (1989)) describe oxa-cephem compounds having a substituent at position 2 of the oxa-cephem skeleton. However, these compounds do not have a catechol group at position 3 of the oxa-cephem skeleton.
The present applicant has filed patent applications of cephem compounds having catechol type substituents (e.g., International Publication No. 2010/050468 pamphlet; International Publication No. 2011/125966 pamphlet; International Publication No. 2011/125967 pamphlet and International Publication No. 2011/136268 pamphlet). However, these applications do not disclose a compound having a substituent at position 2 of the cephem skeleton.